This proposal represents a concerted effort to study the determinants of susceptibility of the mammary gland to chemical carcinogenesis. We propose to make an in-depth investigation to elucidate the relationship between cell proliferation, differentiation and function, and mammary carcinogenesis. It is believed that such studies will lead to an understanding of how pregnancy confers protection of the mammary gland against carcinogenesis. First, we will determine whether protection of the mammary gland against the effect of a carcinogen is related to the age at which pregnancy occurs. Second, we wish to determine whether pregnancy-induced resistance to carcinogenesis of the mammary gland is reversible and, finally, efforts will be made to identify the cellular factors which regulate the sensitivity of mammary cells to carcinogenesis and then to elucidate how pregnancy alters these cellular factors to cause inhibition of carcinogenesis. We wish to test the hypothesis that involuted mammary cells are unable to respond to the effect of hormonal stimuli for cell replication, that these cells respond instead by increased functional activity without DNA replication. Under these circumstances, a carcinogen fails to induce tumorigenesis. Specifically, we will investigate: the cell proliferation pattern in pubertal and involuted mammary glands, particularly pertaining to response to hormonal and carcinogenic stimuli; whether there is an alteration in the hormone receptor mechanism that may account for the changes in response to ovarian cycle in mammary gland from parous rats; the interaction of the carcinogen with the "differentiated, functional" and the "stem" cells of the mammary gland.